Elevated lead (Pb) body burden still impacts almost 9% of U.S. children and >40% of children in some underdeveloped countries. Its association with cognitive deficits in children and in elderly men and women, and with delinquency and aggression, makes it a more pervasive public health problem than has generally been appreciated. Our neurochemical and behavioral studies over the past funding period show that chronic postweaning Pb appears to target the mesolimbic dopamine (DA) system, based on effects observed in its terminal projection region, the nucleus accumbens (NAC). NAC, however, is considered a limbic-motor interface, integrating information via glutamatergic projections from hippocampus and prefrontal cortex, two regions well known to mediate cognitive function. At the same time, Pb also produces a widespread inhibition of glutamatergic NMDA receptors. NMDA inhibition has been shown in prefrontal cortex and NAC to enhance activation of non-NMDA AMPA/kainate excitatory amino acid receptors. The proposed studies therefore test the hypothesis that Pb-induced behavioral impairments and neurochemical changes in mesolimbic systems actually derive from preferential AMP/kainate receptor activation of the glutamatergic projections from hippocampus and prefrontal cortex, to NAC. This hypothesis predicts that hippocampal and prefrontal glutamatergic projections to NAC should be critical in mediating behaviors known to be altered by Pb. Specific Aims 1 and 2 will thus determine whether disconnection of these projections also disrupts these behaviors, and whether preferential AMPAergic activation of these projections can mimic the behavioral toxicity of Pb in normal rats, using two behavioral baselines reliably altered by Pb: fixed interval performance and a repeated learning paradigm. Specific Aim 3 tests the associated prediction that AMPA antagonists in these projection regions should reverse these Pb-induced behavioral impairments. Specific Aim 4 seeks to determine whether preferential AMPAergic activation of these projections reproduces in normal rats the increases in evoked DA overflow in NAC associated with Pb, and if AMPA antagonists can reverse these increases in Pb-treated rats. To determine the extent to which these mechanisms generalize to human Pb exposure and whether they may be exacerbated by exposures earlier in development, Specific Aims 2 and 4 compare effects of preweaning, postweaning and continuous Pb exposures. These experiments will significantly advance our understanding of the control of complex operant cognitive behaviors by hippocampal and prefrontal projection circuits and the mechanisms by which Pb disrupts them. They will further define the comparative roles of NMDA and AMPA/kainate receptors in these projections and their interactions with DA systems, allowing rational behavioral and therapeutic approaches to mesolimbic system dysfunctions.